Gene expression profiles reflect sclerosing cholangitis activity in abcb4 (−/−) mice

Abstract

Objective. Abcb4 (−/−) mice secrete phosphatidylcholine-deficient bile and develop sclerosing cholangitis (SC), a condition that involves differential hepatic transcription of genes governing inflammation, tissue remodelling and fibrosis. The objective of this study was to test the hypothesis that genes involved in the regulation of tissue inflammation and fibrosis display transcription rates that parallel differences in abcb4 (−/−) SC activity. The activity of abcb4 (−/−) SC can be altered through dietary intervention: abcb4 (−/−) mice fed cholic acid (CA) display high SC activity, whereas ursodeoxycholic acid (UDCA)-fed mice display low SC activity. Material and methods. Differential hepatic transcription of genes was measured in abcb4 (−/−) mice maintained on CA- and UDCA-supplemented diets using cDNA microarrays. Abcb4 (+/+) mice served as controls. Differential transcription of selected genes was verified by real-time polymerase chain reaction. Liver tissue pathology was quantified by histopathology scoring. Result. Histopathology score, reflecting increased inflammation and fibrosis, was increased in CA-fed mice compared with UDCA-fed mice. cDNA microarray analysis showed up-regulation of 1582 genes in livers of CA-fed mice in contrast to 573 genes in UDCA-fed mice. Differential transcription of Ccl2, Ccl20, Cxcl10, Nfκb1, Nfκb2, Tgfβ1, Tgfβ2, Sparc, Ctgf, Lgals3, Elf3, Spp1, Pdgfa, Pdgfrb, Col1a1, Col1a2 and Col4a1 genes paralleled the unequal SC activities of CA- and UDCA-fed abcb4 (−/−) mice. Conclusions. The numbers of differentially transcribed genes and the transcriptional activity of genes relating to inflammation, tissue remodelling and fibrosis parallel disease activity in CA- and UDCA-fed abcb4 (−/−) mice harbouring SC. Data on their hepatic transcription can gauge SC disease activity.

• Abcb4
• cholic acid
• chronic cholangitis
• mdr2
• stellate cells
• ursodeoxycholic acid